Project 3, Airway Biology of Acute Environmental Asthma in Humans will examine the effect of environmental endotoxin on acute exacerbation of asthma. Epidemiological studies have shown that environmental particulate matter (PM) and endotoxin (a component of PM) are associated with increased occurrences of asthma exacerbation and wheeze. Published reports from our group and others demonstrate that endotoxin induce an innate response in the airway characterized by changes in monocyte/macrophage biology and influx of airway neutrophils. We have also shown that these responses correlate well to expression of CD14 on airway macrophages. Low levels of endotoxin prime the airway such that response of allergic asthmatics to allergens is enhanced, and lead to the general hypothesis that priming of the airway by pollutants via innate immune mechanisms to respond to additional pollutants or allergens is a central process by which environmental asthma is initiated. Though it is clear that environmental endotoxin induces asthma exacerbation, there is a significant gap in knowledge regarding the mechanisms which modulate inflammation due to this environmental irritant. Recent preliminary data from our group suggest that IL-1 (3 is an important modulator of endotoxin induced events in the airway. The recently discovered members of the CATERPILLER family of immune regulatory proteins play an important role in regulating IL-1p induced inflammation and we hypothesize that CATERPILLER genes are important in regulating pollutant induced asthma. Signals from pathogen associated molecular patterns entities (such as endotoxin) activate cryopyrin and NALP1, and induce the loss of the negative regulator protein monarch-1. In addition to being activated by PAMPs, cryopyrin is activated by endogenous ligands such as ATP (which is released by inflamed/injured airway cells) after ligation to the P2X7 receptor. Projects 1 and 2 focus on the role that these molecules have in mediating airway responses to LPS, differences in these responses observed between allergen sensitized and naTve mice, and the priming effect of endotoxin on response to allergen. This aims of this project will be to examine the effect of allergen and endotoxin-induced inflammation on expression of CATERPILLAR regulators, P2X7 receptors and other molecules which enhance innate and immune response by airway monocytes, granulocytes and epithelial cells in allergic asthmatics, the modification of response to LPS by allergic inflammation, and the effect of anti-inflammatory therapy on these processes.